Crystal of compound X7 hydrochloride and its preparation method and application

This application is a U.S. national stage filing under 35 U.S.C. § 371 from International Application No. PCT/CN2021/113018, filed on 17 Aug. 2021, and published as WO2022/037580 on 24 Feb. 2022, which claims the benefit under 35 U.S.C. 119 to Chinese Application No. 202010831132.4, filed on 18 Aug. 2020, the benefit of priority of each of which is claimed herein, and which applications and publication are hereby incorporated herein by reference in their entirety.

The present invention relates to the technical field of pharmaceutical chemistry, in particular, to the crystal of compound X7 hydrochloride and its preparation method and application.

The compound X7 hydrochloride has a strong vasodilator effect, a definite hypotensive effect with a quick onset, accompanied by a mild heart rate slowing effect, which does not affect the cardiac conduction system, and it produces a beneficial effect on hemodynamics. Its long-term administration has a protective effect on organ damage caused by hypertension. As a pharmaceutical active ingredient, the crystal structure often affects the chemical and physical stability of the drug. Different crystallization and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by other crystal forms. Therefore, further investigation is necessary to find crystals with better physical and chemical properties.

The present invention proposes a crystal of compound X7 hydrochloride and its preparation method and application. This crystal of compound X7 hydrochloride has better physical and chemical properties.

Based on the above purpose, one aspect of the invention provides a crystal of compound X7 hydrochloride, and the 2θ diffraction angle of the X-ray powder diffraction diagram of the crystal has characteristic diffraction peaks in the range of 5°˜35°.

Wherein the structural formula of the compound X7 hydrochloride is shown in formula (I):

In the preferred embodiment of the invention, the crystal of compound X7 hydrochloride comprises crystal form A, and the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form A exhibits characteristic diffraction peaks at 15.12±0.2°, 11.57±0.2°, and 21.03±0.2°.

Preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form A exhibits characteristic diffraction peaks at 26.01±0.2°, 17.92±0.2°, and 27.89±0.2°.

More preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form A exhibits characteristic diffraction peaks at 25.34±0.2°, 19.96±0.2°, 12.49±0.2°, 30.64±0.2°, 7.57±0.2°, 31.11±0.2°, and 9.99±0.2°.

In the preferred embodiment of the invention, the thermogravimetric analysis diagram of crystal form A exhibits a weight: loss of 0.8±0.5% in the range of 30.0˜155.0° C.

And/or, the differential scanning calorimetry of crystal form A exhibits endothermic peaks in the range of 210.0˜220.0° C.

And/or, crystal form A is crystal free.

In the preferred embodiment of the invention, the crystal of compound X7 hydrochloride comprises crystal form B, and the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form B exhibits characteristic diffraction peaks at 7.38±0.2°, 13.19±0.2°, and 16.99±0.2°.

Preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form B exhibits characteristic diffraction peaks at 25.57±0.2°, 14.48±0.2°, and 25.05±0.2°.

More preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form B exhibits characteristic diffraction peaks at 19.86±0.2°, 23.08±0.2°, and 21.38±0.2°.

2. In the preferred embodiment of the invention, the thermogravimetric analysis diagram of crystal form B exhibits a weight loss of 8.0˜12.0% in the range of 29.0˜72.0° C.

And/or, the differential scanning calorimetry of crystal form B exhibits endothermic peaks in the ranges of 60.0˜80.0° C. and 195.0˜215.0° C. and exothermic peaks in the range of 125.0˜145.0° C.

And/or, the crystal form B is hydrate.

In the preferred embodiment of the invention, the crystal of compound X7 hydrochloride comprises crystal form C, and the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form C exhibits characteristic diffraction peaks at 8.26±0.2°, 15.68±0.2°, and 14.03±0.2°.

Preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form C exhibits characteristic diffraction peaks at 21.25 10±0.2°, 25.30±0.2°, and 13.43±0.2°.

More preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form C exhibits characteristic diffraction peaks at 15.91±0.2°, 207.59±0.2°, 23.64±0.2°, 28.70±0.2°, 16.59±0.2°, 21.73±0.2°, 19.28±0.2°, 2.13±0.2°, 38.46±0.2°, 33.57±0.2°, 25.78±0.2°, 30.31±0.2°, and 34.30±0.2°.

In the preferred embodiment of the invention, the thermogravimetric analysis diagram of crystal form C exhibits a weight loss of 1.5˜2.5% in the range of 27.0˜190.0° C.

And/or, the differential scanning calorimetry of crystal form C exhibits endothermic peaks in the range of 128.0˜460.0° C. and exothermic peaks in the range of 201.0˜210.0° C.

And/or, the crystal form C is crystal free.

In the preferred embodiment of the invention, the crystal of compound X7 hydrochloride comprises crystal form D, and the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form D exhibits characteristic diffraction peaks at 15.69±0.2°, 24.98±0.2°, and 8.69±0.2°.

Preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form D exhibits characteristic diffraction peaks at 15.12±0.2°, 12.67±0.2°, and 22.11±0.2°.

More preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form D exhibits characteristic diffraction peaks at 21.40±0.2°, 25.62±0.2°, 27.89±0.2°, 19.39±0.2°, 18.38±0.2°, 6.28±0.2°, 13.85±0.2°, 27.39±0.2°, 28.94±0.2°, 18.88±0.2°, 35.84±0.2°, 33.36±0.2°, 31.68±0.2°, and 30.65±0.2°.

In the preferred embodiment of the invention, the thermogravimetric analysis diagram of crystal form D exhibits a weight loss of 2.0˜2.5% in the range of 30.0˜190.0° C.

And/or, the differential scanning calorimetry of crystal form D exhibits endothermic peaks in the range of 200.0˜210.0° C.

And/or, the crystal form D is crystal free.

In the preferred embodiment of the invention, the crystal of the compound X7 hydrochloride comprises crystal form E, and the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form E exhibits characteristic diffraction peaks at 23.08±002©, 19.05±0.2°, and 13.01±0.2°.

Preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form E exhibits characteristic diffraction peaks at 26.12±0.2°, 21.56±0.2°, and 11.81±0.2°.

More preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form E exhibits characteristic diffraction peaks at 15.36±0.2°, 23.83±0.2°, and 24.75±0.2°.

Further preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form E exhibits characteristic diffraction peaks at 18.75±0.2°, 9.57±0.2°, 9.81±0.2°, 22.71±0.2°, 24.28±0.2°, 16.76±0.2°, 28.19±0.2°, 19.72±0.2°, 20.77±0.2°, and 16.40±0.2°.

In the preferred embodiment of the invention, the crystal of compound X7 hydrochloride comprises crystal form F, and the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form F exhibits characteristic diffraction peaks at 11.74±0.2°, 5.77±0.2°, and 15.66±0.2°.

Preferably, the 2θ diffraction angle of the X-ray powder diffraction diagram of crystal form F exhibits characteristic diffraction peaks at 23.79±0.2°, 26.51±0.2°, 13.81±0.2°, 28.49±0.2°, 30.11±0.2°, 20.25±0.2°, 17.74±0.2°, 8.82±0.2°, 18.79±°, and 33.04±°.

In the preferred embodiment of the invention, the thermogravimetric analysis diagram of crystal form F exhibits a weight loss of 8.0˜8.5% in the range of 25.0˜90.0° C.

And/or, the differential scanning calorimetry of crystal form F exhibits endothermic peaks in the ranges of 50.0˜80.0° C., 190.0˜205.0° C., and 206.0˜215.0° C.

And/or, the crystal form F is hydrate.

Based on the same inventive concept, another aspect of the invention provides a method for preparing the crystal of compound X7 hydrochloride, (a) the preparation method of crystal form A comprises:

Dissolving the compound X7 hydrochloride in the first good solvent, then adding the first anti-solvent drop-wise, and collecting the precipitated solid to obtain crystal form A.

Preferably, the first good solvent is selected from at least one of methanol, trichloromethane, dimethyl sulfoxide, or N-methylpyrrolidone.

And/or, preferably, the first anti-solvent is selected from at least one of acetone, isopropyl acetate, 2-methyltetrahydrofuran, methyl isobutyl ketone, toluene, isopropanol, methyl tert-butyl ether, acetonitrile, or ethyl acetate.

Or, (b) the preparing method of crystal form A comprises:

Placing the open container containing compound X7 hydrochloride in the sealed container containing the first solvent, letting it stand still, and collecting the solid to obtain crystal form A.

Preferably, the first: solvent is selected from at: least one of water, dichloromethane, ethanol, methanol, acetonitrile, tetrahydrofuran, trichloromethane, acetone, dimethyl sulfoxide, ethyl acetate, 1,4-dioxane, or isopropanol.

Preferably, the “letting it stand still” means 6 to 10 days at room temperature.

Or, (c) the preparing method of crystal form A comprises:

Placing compound X7 hydrochloride in a container, adding a second solvent to dissolve compound X7 hydrochloride in the second solvent, preparing a clear solution, then slowly volatilizing, and collecting the solid to obtain crystal form A.